Nectin-4 expression in a subset of cutaneous adnexal carcinomas: A potential target for therapy with enfortumab vedotin.

BACKGROUND: Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4 that is used to treat urothelial carcinoma. Nectin-4 is inherently expressed in the skin and adnexal structures. Since therapeutic options for cutaneous adnexal carcinomas are limited, we sought to evaluate Nectin-4 expression in adnexal carcinomas and benign adnexal neoplasms to identify tumors that are potentially targetable with EV. METHODS: Eight sebaceous carcinomas (seven periocular and one lymph node metastasis), eight digital papillary adenocarcinomas, seven squamoid eccrine ductal carcinomas, eight poromas, eight trichilemmomas, and seven sebaceous adenomas were subjected to immunohistochemical staining for anti-Nectin-4 antibody. H-scores for Nectin-4 expression were calculated. RESULTS: Benign adnexal neoplasms had a significantly lower mean (±SD) Nectin-4 H-score (142.6 ± 39.1) than did the adnexal carcinomas (198 ± 90.8; p = 0.006). Nectin-4 was expressed in 91% (21/23) of adnexal carcinomas. Sebaceous carcinomas frequently exhibited high expression of Nectin-4 (88% [7/8]), with a mean (±SD) H-score (258.1 ± 58.4) significantly higher than those for digital papillary adenocarcinomas (197.5 ± 52.5; p = 0.035) and squamoid eccrine ductal carcinomas (131.4 ± 114.1; p = 0.031). Sebaceous carcinomas also had significantly higher H-scores than did sebaceous adenomas (186.4 ± 25.0; p = 0.013). CONCLUSIONS: Increased Nectin-4 expression in a subset of cutaneous adnexal carcinomas, particularly sebaceous carcinomas, reveals that EV is a potential therapeutic option for these tumors.

Lacrimal Gland Adenocarcinoma Clinicopathologic Features and Outcomes Compared With Those of Lacrimal Gland Adenoid Cystic Carcinoma.

PURPOSE: Lacrimal gland (LG) adenocarcinomas (ACs) are rare, with limited data. We compared clinicopathologic features and local recurrence, distant metastasis, and survival rates between LG AC and LG adenoid cystic carcinoma (ACC). METHODS: The records of LG AC patients treated from 2008 to 2022 and LG ACC patients treated from 1998 to 2022 at the same center were retrospectively reviewed. RESULTS: The study included 20 patients with AC; 10 de-novo AC, 10 ex-pleomorphic AC; and 51 ACC patients. The median age at diagnosis was 61 years for de-novo AC, 54 years for ex-pleomorphic AC, and 45 years for ACC. All groups had male predominance. The initial T category was T2 in 50% (5/10) of de-novo ACs; 60% (6/10) of ex-pleomorphic ACs; and 59% (30/51) of ACCs. Perineural invasion was present in 33% (5/15) of ACs and 90% (45/50) of ACCs ( p < 0.001). Of the 20 AC patients, 14 had eye-sparing surgery; 4 had orbital exenteration; and 2 had unresectable disease. All AC patients received postoperative radiotherapy and 15 (75%) received concurrent chemotherapy. Fourteen AC patients were tested for human growth factor receptor 2 expression, and 10 (71%) were human growth factor receptor 2 positive; 5 received human growth factor receptor 2-targeted therapy. AC and ACC had similar 5-year recurrence rates (20% and 33%, respectively, p = 0.31) and metastasis rates (20% and 34%, respectively, p = 0.30). de-novo AC, ex-pleomorphic AC, and ACC had similar 5-year disease-specific survival rates (80%, 79%, and 81%, respectively, p > 0.99). CONCLUSIONS: LG AC and ACC have similar baseline clinicopathologic features, except that perineural invasion is more common in ACC, and similar recurrence, metastasis, and survival rates. Human growth factor receptor 2-targeted therapy may be appropriate in some patients with LG AC.

Complete Response to Immunotherapy Using Pembrolizumab in a Patient With Conjunctival Squamous Cell Carcinoma With Nodal Metastasis.

A 92-year-old woman presented with a large bulbar conjunctival mass in the OD. She also had a palpable parotid mass which on fine needle aspiration biopsy confirmed to be metastatic squamous cell carcinoma. The conjunctival mass was biopsied to confirm the diagnosis of squamous cell carcinoma with positive programmed cell death ligand 1 expression and a high tumor mutation burden. She was treated with pembrolizumab and had complete resolution of the conjunctival mass and the associated parotid metastasis after just 2 cycles of treatment. This case underscores the promising role of immune checkpoint inhibitors in the treatment of conjunctival squamous cell carcinoma, especially when surgery is associated with significant ocular morbidity, in patients who may not be good surgical candidates, or in patients with metastasis.

The combined profunda artery perforator-gracilis flap for immediate facial reanimation and resurfacing of the radical parotidectomy defect.

BACKGROUND: A radical parotidectomy with facial nerve sacrifice results in facial nerve paralysis as well as a volume and often cutaneous defect. Prior experience with nerve grafting and static suspension has yielded suboptimal results. The present report aims to examine the feasibility and outcomes of a combined free gracilis and profunda artery perforator (PAP) flap from a single donor site can reconstruct these extensive defects and potentially restore dynamic facial reanimation even in the setting of adjuvant radiation. PATIENTS AND METHODS: A retrospective review of 10 patients (6 males and 4 females) was performed from 2016 to 2020 that underwent a combined PAP-gracilis reconstruction of a radical parotidectomy defect. All patients (mean age: 71.3 years; range: 52-83 years) received adjuvant radiation. A chimeric PAP-gracilis flap requiring a single microvascular anastomosis was performed in three patients while the remaining patients underwent a double free flap reconstruction. RESULTS: The gracilis flap was innervated using the facial nerve stump, spinal accessory and massecteric nerve in three patients each. One patient's gracilis was innervated using the hypoglossal nerve. Three patients also underwent nerve grafting of the facial nerve. One patient was taken back to the operating room for a hematoma in the recipient site and there were not flap losses of either the PAP or gracilis flap. Two patients had delayed wound healing of the donor site that healed with conservative management. Average follow-up was 11.1 months (range: 8.1-19.5 months). Six patients were able to achieve dynamic animation while the others obtained a static reconstruction and did not have issues with drooling, eating, or speaking. CONCLUSIONS: Immediate functional muscle transfer can potentially restore dynamic facial reanimation even following radiation. Combining reconstruction using a PAP-gracilis flap addresses the soft tissue deficit and facial paralysis using a single donor site in a single operation.

Treatment patterns and outcomes of palliative systemic therapy in patients with salivary duct carcinoma and adenocarcinoma, not otherwise specified.

BACKGROUND: Salivary duct carcinoma (SDC) and adenocarcinoma, not otherwise specified (adeno-NOS), are rare salivary gland cancers. Data on the efficacy of systemic therapy for these diseases are limited. METHODS: Data were retrospectively collected from patients seen at The University of Texas MD Anderson Cancer Center during 1990 to 2020. Objective response rate (ORR) was assessed per RECIST v1.1. Recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) were assessed by Kaplan-Meier method. Cox regression model was performed to identify predictors of survival. RESULTS: The analysis included 200 patients (110 with SDC and 90 with adeno-NOS); 77% had androgen-receptor-positive tumors and 47% had HER2-positive (2+-3+) tumors. Most patients without metastasis at diagnosis underwent surgery (98%) and postoperative radiotherapy (87%). Recurrence rate was 55%, and the median RFS was 2 years. Nodal involvement and positive surgical margins were associated with recurrence (P < .005). Among patients with stage IVA-B disease, addition of systemic therapy to local therapy increased OS (P = .049). The most-used palliative-systemic-therapy regimen was platinum doublet ± trastuzumab. For first-line therapy, the ORR and median PFS were 33% and 5.76 months, respectively, and for second-line therapy the ORR and median PFS were 25% and 5.3 months, respectively. ORR and PFS were higher with HER2-targeting agents. Median OS was 5 years overall and 2 years for metastatic disease. Older age and higher stage were associated with worse OS. CONCLUSION: Adding systemic therapy to local therapy may improve outcomes of patients with locoregionally advanced SDC or adeno-NOS. Except for HER2-targeted therapy, response to palliative systemic therapy is limited. These findings may be used as a benchmark for future drug development.

Outcomes of orbital exenteration for craniofacial lesions.

BACKGROUND: Orbital exenteration (OE) is an ablative procedure used in the management of malignancies of the orbit of either primary or secondary origin. Publications evaluating this procedure have suffered from small patient numbers, heterogeneity of pathologies, and poor patient follow-up. The purpose of this study was to assess patient outcomes in a large cohort of patients undergoing OE at a tertiary cancer center. METHODS: A retrospective review was conducted of 180 consecutive patients who underwent OE at the authors' institution. Overall survival (OS) was the primary end point measured in the study. Time to locoregional recurrence (progression-free survival [PFS]) and disease-free survival were secondary end points. RESULTS: Between the years 1993 and 2011, 180 consecutive patients received OE for craniofacial malignancy at the authors' institution. The median follow-up for the cohort was 9.7 years (116 months). The median OS was 73 months, and the median PFS was 96 months. The presence of perineural invasion was associated with shorter OS (P = .01) and PFS (P < .01). Magnetic resonance imaging was predictive of perineural invasion (P < .01). Positive margins were associated with shorter PFS than negative margins (P < .01) but with no change in OS (P = .15). The overall complication rate was 15%. The major complication rate (Clavien-Dindo 3b or greater) was 2.8% (n = 5), and there was 1 death observed (0.6%). CONCLUSIONS: Used judiciously in the setting of a multidisciplinary management plan, OE for tumor control is a safe therapy. LAY SUMMARY: Between the years 1993 and 2011, 180 consecutive patients received orbital exenteration for craniofacial malignancy at the MD Anderson Cancer Center. The median follow-up for the cohort was 9.7 years. The presence of perineural invasion was associated with shorter overall survival (P = .01) and progression-free survival (P < .01). Magnetic resonance imaging was predictive of perineural invasion (P < .01). Positive margins were associated with shorter progression-free survival than negative margins (P < .01). The overall complication rate was 15%. The major complication rate (Clavien-Dindo 3b or greater) was 2.8% (n = 5).

Surgical and Ophthalmologic Outcomes of Reconstruction in Patients Treated With Eye-Sparing Surgery and Radiation Therapy for Tumors of the Lacrimal Drainage Apparatus.

INTRODUCTION: Tumors involving the lacrimal drainage apparatus can be effectively treated with oncologic eye-sparing resection, immediate reconstruction, and adjuvant radiation. The extirpative technique is well described, whereas the reconstructive approach and outcomes are limited and largely anecdotal. The present study describes the largest series in the literature evaluating outcomes after reconstruction after globe-preserving oncologic resection. METHODS: A retrospective review was performed for all patients undergoing reconstruction after resection of lacrimal gland tumors from 2008 to 2019. Reconstruction and ophthalmologic outcomes were assessed. RESULTS: Of the 17 patients included, 2 underwent complex repair, 6 were reconstructed with a locoregional flap, and 9 underwent free flap reconstruction. All patients were treated with adjuvant radiation therapy. The median follow-up was 19 months (range, 5-126 months). Defects reconstructed with free flaps had lower rates of wound dehiscence and fistula formation compared with those reconstructed with other techniques (11% vs 25%, P = 0.45). Patients undergoing reconstruction with free tissue transfer also tended to have lower rates of ectropion, keratopathy and decreased visual acuity compared with those undergoing nonmicrosurgical reconstruction (33% vs 50%, P = 0.48; 11% vs 38%, P = 0.20; 56% vs 75%, P = 0.40, respectively). These differences were not statistically significant. CONCLUSIONS: This is the first study to compare reconstructive and functional outcomes of nonmicrosurgical reconstruction and microsurgical free tissue transfer in the setting of eye-sparing surgery for tumors of the lacrimal drainage apparatus. Although various reconstructive options are feasible, microsurgical free tissue transfer is often used at our center and is associated with reliable outcomes.

Multidisciplinary Management of Orbital Metastasis and Survival Outcomes.

PURPOSE: To study the multidisciplinary management and survival outcomes of orbital metastasis (OM). METHODS: All patients with a diagnosis of OM treated during 1999-2019 were included. Clinical data were retrospectively collected and analyzed. RESULTS: The study included 118 patients, 71 females and 47 males, with a median age of 61 years. The most common primary tumor types were breast carcinoma (43 patients), melanoma (17), and lung (13), thyroid (7), renal cell (6), and neuroendocrine carcinoma (6). Ninety-six patients had a known history of cancer at OM diagnosis. The median time from diagnosis of primary cancer to OM was 31 months (range, 0-304). In 22 patients, OM was the first sign of cancer. In 47 patients, the orbit was the only site of metastasis. The most common presenting features were restricted by extraocular motility (77 patients) and proptosis (61). Eight patients had enophthalmos. OM was diagnosed based on clinical history and imaging studies in 81 patients and orbital biopsy in 37. One hundred nine patients were treated with chemotherapy and immunotherapy, 75 with radiation, and 21 with palliative surgical resection. Eighty-two patients died during follow up. The median overall survival (OS) time after diagnosis of OM was 17 months (95% CI: 12-28). OM from renal cell carcinoma was associated with the best and OM from thyroid cancer with the worst OS. Patients with breast cancer had longer median survival (28 months; 95% CI: 15-60) than patients with lung, melanoma, neuroendocrine, or thyroid cancer. CONCLUSION: In this large series, breast cancer and melanoma were the most common causes of OM. Most patients had a known history of cancer at OM diagnosis and did not require orbital biopsy to confirm the diagnosis. Patients with renal cell carcinoma and breast carcinoma had the best prognosis after diagnosis of OM.

Prognostic Factors for Orbital Exenteration, Local Recurrence, Metastasis, and Death From Disease in Conjunctival Squamous Cell Carcinoma.

PURPOSE: Information regarding risk of metastasis and disease-related death (DD) from conjunctival squamous cell carcinoma (SCC) is relatively scarce. We explored prognostic factors for orbital exenteration, local recurrence, nodal metastasis, and DD in patients with conjunctival SCC. DESIGN: Retrospective cross-sectional study. METHODS: All consecutive patients with conjunctival SCC treated by the senior author at MD Anderson Cancer Center during1999-2018 were included. Survival curves were estimated using the Kaplan-Meier method, and survival differences were assessed using 2-sided log-rank tests. RESULTS: The study included 44 patients (24 men, 20 women); median age was 64 years (range, 40-90). T categories at presentation were as follows: Tis, 20 patients; T2, 8; T3, 9; and T4, 7. Eighteen patients (41%) had tumors exclusively in the bulbar conjunctiva; 26(59%) had nonbulbar conjunctival involvement. The median follow-up time was 29.2 months (95% CI: 21.8-44.3). Orbital exenteration was performed in 10 cases (23%) and was associated with T3 or more advanced disease at presentation (p < 0.001). Seven patients developed local recurrence during follow up. History of organ transplant correlated with local recurrence and orbital exenteration (p < 0.01). Nodal metastasis was present in 1 patient at presentation and occurred in 3 patients during follow up, for an overall nodal metastasis rate of 9% (4/44). By end of follow up, 2 patients had died of disease, 4 had died of other causes, and 38 were alive with no evidence of disease. The results suggest that both orbital exenteration and nodal metastasis are independent variables associated with DD. CONCLUSIONS: In patients with conjunctival SCC, orbital exenteration and nodal metastasis are associated with DD and organ transplantation is associated with orbital exenteration.

Carcinoid Tumors of the Orbit and Ocular Adnexa.

PURPOSE: Well-differentiated neuroendocrine or carcinoid tumors are found most commonly in the gastrointestinal tract. When metastatic to the orbit, they tend to have a propensity for the extraocular muscles. The purpose of this study was to better understand the diversity in presentation of orbital carcinoid disease and to determine predictors for survival. METHODS: In this observational cross-sectional cohort study, data from 8 tertiary orbital practices were compiled. Demographic, clinical, pathologic, American Joint Committee on Cancer stage and grade, imaging, and management data were extracted for all the patients. Descriptive statistics were calculated. Subgroups were compared utilizing analysis of variance analyses and Kaplan-Meier curves. Time to progression and disease-specific and overall mortality were calculated. Comparisons were performed for the following a priori pairs: unknown versus known primary tumor, single versus multiple extraocular muscle involvement, unilateral versus bilateral orbital disease, extraocular muscle versus other orbital involvement, and excisional versus incisional surgery. RESULTS: A total of 28 patients with carcinoid tumors of the orbit were identified. Of these, 57.1% of patients were female, the mean age at diagnosis of the primary tumor was 58.8 years and the mean age at diagnosis of orbital disease was 62.6 years. At primary presentation, all patients were American Joint Committee on Cancer stage III or IV and 21.4% demonstrated carcinoid syndrome. Muscle involvement was noted in 78.6% of patients, and of these, 72% were noted to have single muscle disease. Eight patients had no primary tumor identified; 3 of these 8 demonstrated disseminated disease at the time of diagnosis. The overall 5-year survival rate was 81.8% from diagnosis of primary tumor and 50% from diagnosis of orbital disease. Subgroup analysis revealed that patients with unilateral orbital disease when compared with bilateral orbital disease had a longer progression-free survival and time to death from all causes (p = 0.025). Patients with disease localized to the orbit at presentation had longer time to death than those with disseminated disease. Treatment with surgery, radiation, or octreotide did not appear to affect survival. Patients managed with systemic chemotherapy had a shorter time of survival than the rest of the group. All other subgroup comparisons were not found to be statistically significant. CONCLUSIONS: Neuroendocrine tumors of the orbit represent a wide spectrum of disease, with some cases being part of disseminated disease, while others being localized presentations. This heterogeneity may be responsible for the slightly higher overall survival in these patients than others with metastatic carcinoid tumors in other locations.

Immune Checkpoint Inhibitor Therapy as an Eye-Preserving Treatment for Locally Advanced Conjunctival Melanoma.

The authors present 2 patients with locally advanced conjunctival melanoma for whom definitive surgery would mean an orbital exenteration with its associated inherent total visual loss and major facial disfigurement. Instead both patients were treated with immune checkpoint inhibitor therapy. In 1 patient neoadjuvant pembrolizumab was used for approximately 12 months and the patient experienced near-total clinical resolution of the conjunctival melanoma. Multiple surgical biopsies of very small residual pigmentation showed pigmented macrophages and a complete pathologic response. In the second patient who presented with a locally advanced and metastatic conjunctival melanoma, significant shrinkage of conjunctival mass was observed after treatment with a combination of ipilimumab and nivolumab for 5 months, and this allowed preservation of the eye and ocular function.

Inverted Papilloma of the Orbit and Nasolacrimal System.

PURPOSE: Periocular inverted papilloma (IP) is a rare, locally aggressive tumor with a propensity for recurrence and malignant transformation. Historically treated via wide excision, this study examines the characteristics and management of periocular IP, comparing those confined to the nasolacrimal system with those invading the orbit. METHODS: An Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant retrospective, comparative case series was conducted in patients with IP of the orbit or nasolacrimal system across 15 clinical sites. RESULTS: Of 25 patients, 22 met inclusion criteria with 9 limited to the nasolacrimal system and 13 invading the orbit. Mean age was 60.4 years, 55% were women, all were unilateral. Mean follow-up was 48 months. Rates of smoking, dust and/or aerosol exposure, human papillomavirus (HPV) status, and inflammatory polyps were elevated compared to rates in the general population (45%, 18%, 18%, and 14%, respectively). Bony erosion on computed tomography scans was statistically significantly associated with orbit-invading IP (p = 0.002). Treatment involved all confined IP undergoing surgery alone while 39% of orbit-invading IP also received radiation therapy and/or chemotherapy (p = 0.054). Orbit-invading IP was more likely to be excised with wide margins than IP confined to the nasolacrimal system (85% vs. 22%, p = 0.007). Overall rates of malignancy, recurrence, and patient mortality from IP were found to be 27%, 23%, and 9%, respectively. CONCLUSIONS: IP invading the orbit typically requires aggressive therapy, while IP confined to the nasolacrimal system may be treated more conservatively. Using risk factors, characteristics, and outcomes, a treatment algorithm was created to guide management.

Whole-exome sequencing for ocular adnexal sebaceous carcinoma suggests PCDH15 as a novel mutation associated with metastasis.

Ocular adnexal sebaceous carcinoma (OASeC) is an aggressive eyelid carcinoma. Analysis of molecular-genetic drivers of this disease could reveal new prognostic markers and actionable targets for treatment. To identify somatically acquired genomic mutations in OASeC and explore their associations with metastasis, whole-exome sequencing on DNA extracted from retrospectively collected tumor samples was performed. Thirty-one patients in two orbital oncology centers with OASeC were included. Sequencing results were analyzed to detect mutations and explore their possible association with metastasis. The median patient age was 64 years. A total of 1780 candidate somatic mutations were identified with median mutation rate of 1.0/Mb (range, 0.2-13.6). The five most commonly mutated genes (as determined by MutSig; q value < 0.25) were TP53 (mutated in 22 cases), ZNF750 (13 cases), RB1 (12 cases), NOTCH1 (8 cases), and PCDH15 (5 cases). Mutations in ZNF750 or NOTCH1 pathway genes were present in 24 (77%) of the 31 cases; there was a trend toward mutual exclusivity of ZNF750 and NOTCH1 mutations. All eight tumors with NOTCH1 mutations also had TP53 and/or RB1 mutations. Four of the five PCDH15 mutations and all four PCDH15 missense mutations were identified in patients with metastatic disease, including one patient with distant metastasis and three with nodal metastasis. PCDH15 was significantly associated with metastasis (P = 0.01). We identified the most commonly mutated genes in a series of OASeCs and found a previously unreported mutation in OASeC, PCDH15 mutation, that was significantly associated with metastasis. NOTCH1 mutation is an actionable mutation; clinical trials targeting this mutation are available throughout the US and could be considered for patients with metastatic NOTCH1-mutant OASeC. TP53, ZNF750, RB1, and PCDH15 mutations are most likely loss-of-function mutations and may have diagnostic and prognostic importance.

Malignant Mixed Tumor (Carcinoma Ex Pleomorphic Adenoma) of the Lacrimal Gland.

PURPOSE: To review the clinical presentation, treatment, and prognosis of patients with malignant mixed tumor (carcinoma ex pleomorphic adenoma) of the lacrimal gland. METHODS: Clinical records and radiographic images were reviewed for patients with malignant mixed tumor of the lacrimal gland treated at the center during 2008-2019. RESULTS: The study included 9 patients (6 men, 3 women) aged 17-66 years (median age, 56 years). Six had primary malignant mixed tumor with no history of orbital lesions, and 3 had previously been diagnosed with pleomorphic adenoma. Tumor, Node, Metastasis classification per the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual were T1aN0M0 in 2 patients, T2aN0M0 in 3 patients, T4bN0M0 in 2 patients, and T4cN0M0 in 2 patients. Two patients underwent orbital exenteration, 6 patients underwent eye-sparing surgery, and 1 patient had an unresectable tumor because of cavernous sinus extension. All patients received radiotherapy (intensity-modulated radiotherapy in 3 and proton therapy in 6). All patients received chemotherapy, 8 concurrently with radiotherapy and 1 after radiotherapy. The median follow-up time was 70 months. At last contact, 6 patients were alive without evidence of disease; 2 had died of disease, 1 of distant metastasis, and the other of cavernous sinus invasion. CONCLUSIONS: The findings suggest that de novo malignant mixed tumor of the lacrimal gland is more common than disease that results from transformation after incomplete resection of lacrimal gland pleomorphic adenoma. Most cases can be treated with eye-sparing surgery and radiation unless skull base extension is present.

Sebaceous carcinoma: evidence-based clinical practice guidelines.

Sebaceous carcinoma usually occurs in adults older than 60 years, on the eyelid, head and neck, and trunk. In this Review, we present clinical care recommendations for sebaceous carcinoma, which were developed as a result of an expert panel evaluation of the findings of a systematic review. Key conclusions were drawn and recommendations made for diagnosis, first-line treatment, radiotherapy, and post-treatment care. For diagnosis, we concluded that deep biopsy is often required; furthermore, differential diagnoses that mimic the condition can be excluded with special histological stains. For treatment, the recommended first-line therapy is surgical removal, followed by margin assessment of the peripheral and deep tissue edges; conjunctival mapping biopsies can facilitate surgical planning. Radiotherapy can be considered for cases with nerve or lymph node involvement, and as the primary treatment in patients who are ineligible for surgery. Post-treatment clinical examination should occur every 6 months for at least 3 years. No specific systemic therapies for advanced disease can be recommended, but targeted therapies and immunotherapies are being developed.

Mohs micrographic surgery for eyelid sebaceous carcinoma: A multicenter cohort of 360 patients.

BACKGROUND: The decision to perform Mohs micrographic surgery (MMS) or wide local excision (WLE) for eyelid sebaceous carcinoma (SC) is controversial. OBJECTIVE: To compare local recurrence, metastasis, and tumor-related mortality of patients with eyelid SC who were initially treated with MMS versus with WLE. METHODS: A multicenter cohort study. Medical records were reviewed for factors associated with recurrence, metastasis, and tumor-related mortality. All eligible patients were followed up. The impact of initial surgical modality on the prognoses were determined by Cox analyses after control for all confounders. RESULTS: Of the 360 patients included in this cohort, 115 (31.9%) underwent MMS as primary resection, whereas 245 (68.1%) underwent WLE. After a median follow-up period of 60.0 months, local recurrence was observed in 18 patients (15.7%) in the MMS group and 97 patients (39.6%) in the WLE group. Metastasis occurred in 9 patients (7.8%) who underwent MMS and 38 (15.5%) who underwent WLE. In all, 6 patients in the MMS group (5.2%) and 21 in the WLE group (8.6%) died of metastatic SC. Multivariable Cox regression indicated that compared with the WLE group, the MMS group exhibited more favorable local recurrence control (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.24-0.73; P = .002) but a comparable metastasis rate (HR, 1.38; 95% CI, 0.60-3.18; P = .453) and comparable tumor-related mortality (HR, 1.70; 95% CI, 0.59-4.93; P = .329). However, this beneficial effect became nonremarkable for patients with pagetoid intraepithelial neoplasia (HR, 1.73; 95% CI, 0.37-8.21; P = .488). LIMITATIONS: Retrospective nature of the study. CONCLUSION: MMS should be proposed for eyelid SC without orbital involvement to achieve recurrence control; however, this surgical procedure did not change the long-term outcomes in terms of metastasis or tumor-related mortality. Patients with pagetoid intraepithelial neoplasia may require adjuvant measures.

Predictors of Local Recurrence for Eyelid Sebaceous Carcinoma: Questionable Value of Routine Conjunctival Map Biopsies for Detection of Pagetoid Spread.

PURPOSE: To identify clinicopathologic factors associated with local recurrence of eyelid sebaceous carcinoma and determine whether routine conjunctival map biopsies are necessary to detect pagetoid spread. METHODS: The authors searched PubMed for articles on eyelid sebaceous carcinoma and pagetoid spread published in English during 1982 to 2018, and they reviewed 99 consecutive patients with eyelid sebaceous carcinoma who underwent surgical excision with frozen section control of margins performed by 1 author (BE) during 1999 to 2017. RESULTS: Local recurrence rates after surgery were 5% to 25% in the literature and 6% in the authors' cohort. Risk factors for local recurrence included T3b (>20 mm) or worse disease according to the AJCC Cancer Staging Manual, eighth edition, pagetoid spread, diffuse growth pattern, and multicentric origin. Pagetoid spread was observed in 8.3% to 70% of patients in the literature and 31% of patients in the authors' cohort. The literature review showed that surgical excision with frozen section control is the mainstay of management of eyelid sebaceous carcinoma, with topical chemotherapy and cryotherapy used in cases with pagetoid spread. The authors found no solid evidence for added value from routine 4-quadrant conjunctival map biopsies, and some studies called into question their accuracy and yield. CONCLUSIONS: In patients with eyelid sebaceous carcinoma, meticulous microscopic margin control is appropriate in all cases and particularly for tumors >20 mm and adjuvant topical chemotherapy should be considered for tumors with conjunctival pagetoid spread. Routine conjunctival map biopsies are not essential, but targeted map biopsies of areas with signs suggestive of pagetoid intraepithelial spread may be appropriate to guide future closer observation or adjuvant treatments.

Change in Eyelid Carcinoma T Category With Use of the 8th Versus 7th Edition of the American Joint Committee on Cancer: Cancer Staging Manual.

PURPOSE: To evaluate the frequency and nature of changes in T category when eyelid carcinomas are staged using the criteria in the 8th edition instead of the 7th edition of the American Joint Committee on Cancer staging manual. METHODS: Following Institutional Review Board approval, a retrospective review was conducted for all consecutive patients with the diagnosis of eyelid carcinoma treated by the senior author from January 2012 through December 2016. After a review of the clinical and pathologic data, each patient's disease was staged using both the 7th-edition and 8th-edition American Joint Committee on Cancer criteria for eyelid carcinomas. Changes in T categories between the 2 staging systems were examined. RESULTS: The review initially identified 167 patients with the diagnosis of eyelid carcinoma. Four patients were excluded because of incomplete or unclear data. The remaining 163 patients included 78 men and 85 women aged 21 to 97 years (median, 68 years). Eighty-two patients had basal cell carcinoma; 35, squamous cell carcinoma; 32, sebaceous carcinoma; 6, mucinous eccrine carcinoma; 3, Merkel cell carcinoma; 3, adenocarcinomas; and 2, adnexal carcinoma. The most common T category according to the 7th-edition criteria was T2a; the most common T category according to the 8th-edition criteria was T1b. Of the 163 patients, 64 (39%) had a lower T category with the 8th-edition than with the 7th-edition criteria, 59 (36%) had a higher T category, and 40 (25%) had the same T category. CONCLUSIONS: Application of the 8th-edition American Joint Committee on Cancer criteria for eyelid carcinoma changed the T category in 75% of patients. In general, the new 8th-edition American Joint Committee on Cancer tumor, node, metastasis (TNM) designations allow for a more objective and consistent designation of the T category.

Impact of Food and Drug Administration Approval of Vismodegib on Prevalence of Orbital Exenteration as a Necessary Surgical Treatment for Locally Advanced Periocular Basal Cell Carcinoma.

PURPOSE: To test the hypothesis that the US Food and Drug Administration approval of vismodegib in early 2012 has reduced the prevalence of orbital exenteration for locally advanced periocular basal cell carcinoma (BCC). METHODS: Following institutional review board approval, the authors reviewed clinical and pathological data of patients with locally advanced periocular BCC (T4 per the eyelid carcinoma classification in the 8th edition of the AJCC Cancer Staging Manual) treated by the senior author during 2006-2018. Patients were grouped into those who were treated before February 2012 ("before vismodegib approval") and those who presented later ("after vismodegib approval"). RESULTS: Forty-two patients with locally advanced periocular BCC were treated during the study period, of whom 31 were men. The median age at presentation was 66 years (range, 43-90). Twenty-two patients had T4a and 20 had T4b tumors. Thirteen patients were treated before and 29 were treated after vismodegib approval. The 2 groups did not differ in age distribution (p = 0.164), sex distribution (p = 0.270), prevalence of recurrent tumor at presentation (p = 0.317), or duration of treatment with vismodegib (p = 0.605). Orbital exenteration was significantly more prevalent in patients treated before vismodegib approval than after (46% vs. 10%, p = 0.016), and vismodegib treatment was significantly more prevalent in patients treated after vismodegib approval than before (when vismodegib was given in clinical trials; 69% vs. 23%, p = 0.008). There was a trend toward more patients retaining their eyes at last follow-up in patients treated after vismodegib approval (83% vs. 54%, p = 0.066). CONCLUSIONS: The prevalence of orbital exenteration as a necessary surgical procedure in patients with a locally advanced periocular BCC has fallen since the Food and Drug Administration approval of vismodegib. Although vismodegib is not specifically approved for organ-sparing, it has changed the authors' practice and enabled eye preservation in patients with locally advanced periocular BCC, who would otherwise require an orbital exenteration.

Extraocular Muscle Enlargement and Thyroid Eye Disease-like Orbital Inflammation Associated with Immune Checkpoint Inhibitor Therapy in Cancer Patients.

PURPOSE: To describe thyroid eye disease (TED)-like orbital inflammatory syndrome in 3 cancer patients treated with immune checkpoint inhibitors. METHODS: All consecutive patients treated by the senior author who were receiving immune checkpoint inhibitors and developed TED-like orbital inflammation were included. RESULTS: Three cancer patients treated with immune checkpoint inhibitors developed orbital inflammation. The first patient was treated with a combination of a cytotoxic T-lymphocyte antigen-4 inhibitor and a programmed cell death protein 1 inhibitor and developed TED-like orbital inflammation with normal thyroid function and antibody levels. The second patient had a previous diagnosis of Graves disease without TED, and developed TED soon after initiating treatment with a programmed cell death protein 1 inhibitor. The third patient developed acute hyperthyroidism with symptomatic TED following treatment with an investigational cytotoxic T-lymphocyte antigen-4 inhibitor agent. All 3 patients were managed with either systemic steroids or observation, with resolution of their symptoms and without the need to halt immune checkpoint inhibitor treatment for their cancer. DISCUSSION AND CONCLUSIONS: TED-like orbital inflammation may occur as a side effect of immune checkpoint inhibitor therapy with anti-cytotoxic T-lymphocyte antigen-4 or anti-PD-1 inhibitors. To the best of their knowledge, this is the first reported case of TED as a result of programmed cell death protein 1 inhibitor monotherapy. All 3 patients were treated with systemic steroids and responded quickly while continuing treatment with immune checkpoint inhibitors for their cancer. With increasing use of this class of drugs, clinicians should be familiar with the clinical manifestations and treatments for this adverse reaction.